{"title":"A Synthetic Circuit Empowering Reprogrammed B Cells for Therapeutic Proteins Expression Regulated by Tumor Detection.","authors":"Audrey Page, Marie Delles, Didier Nègre, Caroline Costa, Floriane Fusil, François-Loïc Cosset","doi":"10.1097/CJI.0000000000000524","DOIUrl":null,"url":null,"abstract":"<p><p>Cancer remains a leading cause of death worldwide, but immunotherapies hold promises to cure it by awaking the patient's immune system to provide long-term protection. Cell therapies, involving the infusion of immune cells, either directly or genetically modified, are being developed to recognize and destroy cancer cells. Here, we explored the potential of a new synthetic circuit to reprogram B cells to cure cancers. This circuit consists in a sensor (a membrane-anchored IgG1), a transducer (a fragment of the NR4A1 promoter) and an effector molecule. Upon recognition of its target, this sensor triggers signaling pathways leading to the activation of the transducer and to effector expression (here, a reporter molecule). We showed that this circuit could discriminate tumors expressing the target antigen from those that did not, in a dose dependent manner in vitro. Going further, we replaced the original membrane-anchored sensor by an immunoglobulin expression cassette that can not only be membrane-anchored but also be secreted depending on B-cell maturation status. This allowed concomitant activation of the circuit and secretion of transgenic antibodies directed against the targeted antigen. Of note, these antibodies could correctly bind their target and were recognized by FcR expressed at the surface of immune cells, which should synergically amplify the action of the effector. The potential of reprogrammed B cells remains to be assessed in vivo by implementing a therapeutic effector. In the future, B-cell reprogramming platforms should allow personalized cancer treatment by adapting both the sensor and the therapeutic effectors to patients.</p>","PeriodicalId":15996,"journal":{"name":"Journal of Immunotherapy","volume":null,"pages":null},"PeriodicalIF":3.2000,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11299900/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Immunotherapy","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1097/CJI.0000000000000524","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/5/22 0:00:00","PubModel":"Epub","JCR":"Q3","JCRName":"IMMUNOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Cancer remains a leading cause of death worldwide, but immunotherapies hold promises to cure it by awaking the patient's immune system to provide long-term protection. Cell therapies, involving the infusion of immune cells, either directly or genetically modified, are being developed to recognize and destroy cancer cells. Here, we explored the potential of a new synthetic circuit to reprogram B cells to cure cancers. This circuit consists in a sensor (a membrane-anchored IgG1), a transducer (a fragment of the NR4A1 promoter) and an effector molecule. Upon recognition of its target, this sensor triggers signaling pathways leading to the activation of the transducer and to effector expression (here, a reporter molecule). We showed that this circuit could discriminate tumors expressing the target antigen from those that did not, in a dose dependent manner in vitro. Going further, we replaced the original membrane-anchored sensor by an immunoglobulin expression cassette that can not only be membrane-anchored but also be secreted depending on B-cell maturation status. This allowed concomitant activation of the circuit and secretion of transgenic antibodies directed against the targeted antigen. Of note, these antibodies could correctly bind their target and were recognized by FcR expressed at the surface of immune cells, which should synergically amplify the action of the effector. The potential of reprogrammed B cells remains to be assessed in vivo by implementing a therapeutic effector. In the future, B-cell reprogramming platforms should allow personalized cancer treatment by adapting both the sensor and the therapeutic effectors to patients.
癌症仍然是全球死亡的主要原因,但免疫疗法有望通过唤醒病人的免疫系统来提供长期保护,从而治愈癌症。目前正在开发的细胞疗法涉及直接或经基因修饰的免疫细胞输注,以识别和摧毁癌细胞。在这里,我们探索了一种新的合成电路的潜力,以重新编程 B 细胞来治疗癌症。该回路由传感器(膜锚定 IgG1)、转换器(NR4A1 启动子片段)和效应分子组成。一旦识别到目标,传感器就会触发信号通路,从而激活转导因子并表达效应分子(这里是一个报告分子)。我们的研究表明,在体外,这种回路能以剂量依赖的方式区分表达靶抗原的肿瘤和不表达靶抗原的肿瘤。此外,我们还用免疫球蛋白表达盒取代了原来的膜锚定传感器,该表达盒不仅可以膜锚定,还可以根据 B 细胞成熟状态分泌。这样就能同时激活电路和分泌针对目标抗原的转基因抗体。值得注意的是,这些抗体可以正确地与目标结合,并被免疫细胞表面表达的 FcR 识别,从而协同放大效应物的作用。重编程 B 细胞的潜力还有待通过治疗效应物在体内进行评估。未来,B 细胞重编程平台应能根据患者的情况调整传感器和治疗效应器,从而实现个性化癌症治疗。
期刊介绍:
Journal of Immunotherapy features rapid publication of articles on immunomodulators, lymphokines, antibodies, cells, and cell products in cancer biology and therapy. Laboratory and preclinical studies, as well as investigative clinical reports, are presented. The journal emphasizes basic mechanisms and methods for the rapid transfer of technology from the laboratory to the clinic. JIT contains full-length articles, review articles, and short communications.